After identifying three different types of resistance to a promising investigational lung cancer drug in a phase I trial, a team of researchers report that new targeted inhibitors and combinations are urgently needed to stay ahead of tumors' constant and varied molecular shape-shifting.

The findings indicate "an underappreciated genomic heterogeneity" in mechanisms of resistance to tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) mutation that drives some cases of non-small cell lung cancer (NSCLC). This was reported in Nature Medicine (2015; doi:10.1038/nm.3854) by the research team that included scientists from Dana-Farber Cancer Institute in Boston, Massachusetts, and from the pharmaceutical company AstraZeneca.

"If resistance that is this complex is constantly evolving before us, it may mean we need multiple targeted therapies in combination to stay ahead of the resistant cancer," said senior author Geoffrey Oxnard, MD, a thoracic oncologist and lung cancer researcher at Dana-Farber.

Since the initial discovery of EGFR mutations in lung cancer 10 years ago, EGFR-targeted therapies such as erlotinib (Tarceva) and afatinib (Gilotrif) have become a fundamental component of lung cancer therapy. Though they can induce dramatic responses, they tend to lose their effectiveness after 9 to 14 months of treatment because drug resistance develops. The most common cause of drug resistance is the development of a second EGFR mutation, T790M.

To fight back, pharmaceutical companies are developing and testing next-generation inhibitors aimed at overcoming the T790M resistance mutation. One such drug, the AstraZeneca compound AZD9291, is showing promise against resistant NSCLC in the ongoing phase I AURA clinical trial.

In this new study, Oxnard and colleagues looked for mechanisms of resistance to AZD9291 by analyzing liquid biopsies from some of the first patients in the clinical trial whose disease progressed despite treatment with the drug. In effect, they were spying on the cancer's next strategy for evading the new drug.

Rather than wait for tumor biopsy samples to become available, scientists captured cell-free DNA shed into the bloodstream by the tumor cells. By testing blood specimens at different times during treatment, the scientists identified that three subtypes of resistance emerged.

In some patients, the cancer cells carrying the T790M mutation acquired an additional EGFR mutation not seen before, C797S, which blocked the AZD9291 from docking to the tumor cells and caused the disease to advance. In some other patients, the drug failed to eliminate cells with the T790M resistance mutation, but the C797S mutation was not the culprit. In still other patients, the cancer cells progressed, but the AZD9291 appeared to have eliminated the T790M resistance mutation, suggesting some other resistance mechanism had taken control.

While EGFR inhibitors have lengthened lives and improved outcomes in patients with advanced NSCLC, experience has shown that resistance inevitably develops. The new study demonstrates the power of liquid biopsies to identify the biological causes of drug resistance and report those mechanisms simultaneously with the release of clinical trial results for a new drug.